Of the routinely tested prenatal markers, a CRP concentration of 5 mg/L or more was the most accurate predictor of EONI, with a sensitivity of 94% and a specificity of 47%. Its predictive value was not improved by including it in a prediction model with WBC count. A CRP concentration of 5 mg/L or more was also associated with both clinical and histological chorioamnionitis, but its predictive values for both outcomes were low.
This study is, to our knowledge, the first to investigate prenatal markers in women with PROM at or after 34 weeks of gestation and the largest prospective cohort study of serum infectious markers in PROM. In a retrospective study including 90 women with PROM from 23 to 41 weeks of gestation, Yoon et al. did not find that either CRP or WBC count had a high predictive value for histological chorioamnionitis .
The ability to predict EONI is a high priority for physicians managing women with PROM, because it is the main cause of neonatal morbidity and mortality when PROM occurs at or after 34 weeks [2, 3]. We used a pre-specified high sensitivity because the aim of this study was to select a population with a very low risk of infection, who could safely avoid systematic active management. The negative predictive value of the test is important, regardless of its specificity. In fact, systematic active management is a strategy with 0% specificity; compared to it, a specificity of 47% is a good result, with nearly half the women safely able to avoid systematic active management.
The choice between immediate active or expectant management for women with PROM from 34 to 37 weeks of gestation remains controversial [6, 7, 22]. Guidelines in many countries advocate active management, mainly because of the risk of neonatal infection [4, 5]. This strategy, however, may increase the rate of moderately preterm birth, which is associated with significant neonatal morbidity [10–12]. It may also increase the cesarean rate among women for whom induction of labor is contraindicated (or unsuccessful). A survey, published in 2004 and including 508 specialists from all 50 of the United States and 13 other countries, showed that the gestational age at which expectant management is rejected in women with preterm PROM varied significantly between respondents: ≥ 34 weeks for 56%, ≥ 35 weeks for 26%, ≥ 36 weeks for 12%, and ≥ 37 weeks for 4.0% . Canadian and Australian surveys show a similar lack of medical consensus on management from 34 to 36 weeks [9, 23].
A recent systematic review included seven randomized controlled trials (690 women) and compared expectant management with early delivery for women with preterm PROM before 37 weeks of gestation (from 25 to 36 weeks) . It identified no difference in neonatal sepsis (RR = 1.3 (0.7, 2.5)) or neonatal respiratory distress (RR = 1.0 (0.7, 1.3)) but found that active management significantly reduced suspected neonatal infection (RR = 0.5 (0.3, 0.8)). Moreover, active management seemed to have no effect on clinical chorioamnionitis (RR = 0.4 (0.2, 1.1)) but was associated with a significant increase in the cesarean rate (RR = 1.5 (1.1, 2.1)) . The authors concluded that there is insufficient evidence about the benefits and disadvantages of immediate delivery, compared with expectant management, for women with preterm PROM. Dare et al. conducted a systematic review that finally included 12 randomized or quasi-randomized trials comparing planned early birth with expectant management in women with PROM at or after 37 weeks of gestation. They concluded that clinical chorioamnionitis was significantly less frequent among women with active management compared with those expectantly managed (RR = 0.7 (0.6, 1.0)), but they observed no difference for neonatal infection (RR = 0.8 (0.6, 1.1)) . From our perspective, these findings underline the uncertainty related to PROM management after 34 weeks of gestation and emphasize the need for a predictive strategy to support individualized care based on the individual risk of infection.
Our methodology was selected to reduce bias as much as possible. We analyzed all continuous variables without dichotomizing them to reduce analytic bias . A bootstrap resampling procedure was used to reduce the over-fit of the statistical model on the study population . To prevent any bias related to gestational age, antibiotic prescriptions, or medical management, we adjusted for these factors in our multivariable model. A meaningful temporal relation between infectious markers and the primary outcome was preserved by including only those women who gave birth within 72 hours after admission . The 35 women who delivered more than 72 hours after admission (8.0%) were excluded from the study. This subgroup's characteristics did not differ significantly from those of women finally included in the study and no differences between the groups were observed for EONI (p = 0.69) or for clinical (p = 0.14) or histological chorioamnionitis (p = 0.06). Nonetheless, we did observe a trend to chorioamnionitis in this group with later deliveries, but lack of power prevented a definitive result. Our study shows that a CRP concentration of 5 mg/L or higher predicts EONI with high sensitivity. Measured routinely at admission, CRP may be useful for selecting a population among whom the risk of EONI contraindicates expectant management. In our study, consideration of CRP at admission would have led to active management of 215 women (54%); including 16 whose infants had EONI (94%). The remaining 184 women could have been managed expectantly: most of them (almost 90%) went into labor spontaneously within 72 hours, and only one neonate had EONI [27, 28]. Although the systematic active management in one center might be considered a limitation of this study, our results suggest that maternal serum CRP could be a safe alternative strategy to systematic active management, especially in cases of previous cesarean deliveries, or breech presentation, or in women with PROM near term. Given that the strategy of systematic active management has 0% specificity and in view of our findings, nearly half the cases could safely avoid systematic active management. Our results call for a randomized trial, to compare immediate systematic active management in PROM at and after 34 weeks of gestation with management according to maternal serum CRP.